Parkinson's disease is a chronic nervous disease characterized by fine, slowly spreading tremors, rigidity, and a characteristic gait. Although the onset of Parkinson's disease may be abrupt, it generally occurs gradually. The initial symptom is often a fine tremor beginning in either a hand or a foot which may spread until it involves all of the members. The duration of Parkinson's disease is indefinite, and recovery rarely if ever occurs. A psychotic confusional state may be seen in the later stages of Parkinson's disease, which is a common and significant source of morbidity.
Levodopa has historically been the medication of choice in treating Parkinson's disease, and there are rarely any failures with levodopa therapy in the early years of treatment. Unfortunately, this response is not sustainable. Most patients develop adverse effects after long-term usage of levodopa; in fact, in some the benefits of treatment wane as the disease progresses.
Several common types of central nervous system dysfunction and peripheral side effects are associated with administration of levodopa. Toxic side effects to the central nervous system include mental changes, such as confusion, agitation, hallucinosis, hallucinations, delusions, depression, mania and excessive sleeping. The symptoms may be related to activation of dopamine receptors in non-striatal regions, particularly the cortical and limbic structures. Elderly patients and patients with cortical Lewy body disease or concomitant Alzheimer's disease are extremely sensitive to small doses of levodopa. However, all patients with Parkinson's disease, regardless of age, can develop psychosis if they take excess amounts of levodopa as a means to overcome "off" periods. This is difficult to remedy, as reducing the dosage of levodopa may lessen its beneficial influence on motor function.
Although dementia may be associated with Parkinson's disease, Alzheimer's disease and Parkinson's disease are pathologically very distinct. Senile dementia of the Alzheimer type (SDAT) is associated with degeneration of the nucleus basalis, and consequently with a cholinergic deficit. Alzheimer's disease is characterized by plaques and neurofibrillary tangles, mainly in the cerebral cortex. Parkinson's disease, on the other hand, is characterized by distinctive Lewy bodies, which are eosinophilic, cytoplasmic structures found mainly in small nuclei at the base of the brain, especially the substantia nigra (dopaminergic cells) and nucleus basalis (cholinergic cells). These two diseases are clinically distinguishable to a competent practitioner.
Clinically, Alzheimer's disease presents with personality change, language errors (difficulties with categorical speed and word generation) and loss of short term memory. The patient is usually alert and attentive. The condition may or may not progress to include mild rigidity of the muscles, although rigidity is never the presenting complaint.
Parkinson's disease, in contrast, presents with muscular rigidity, tremor and imbalance. It may or may not progress to include dementia, although dementia is never the presenting complaint. When dementia is present in Parkinson's patients, it is clinically distinguishable from Alzheimer's disease, and is characterized by inattention, visual hallucinations, and a worsening of the confusion produced by administration of levodopa.
Prior to the introduction of levodopa, anticholinergic drugs had been the conventional treatment of mild parkinsonism since the discovery of belladonna alkaloids in the mid-nineteenth century. However, these drugs have a propensity for exacerbating dementia. Nevertheless, since anticholinergic drugs are known to ameliorate rigidity in the early stages of the disease, the conventionally skilled neurologist would instinctively believe that a procholineric drug might worsen rigidity, as central cholinergic activity appears to be important for memory function in Parkinson's disease. Unfortunately, patients receiving anticholinergic drugs for parkinsonism may experience reversible cognitive deficits so severe as to mimic Alzheimer's disease. Identical memory disturbances have been produced by administration of atropine to patients with either Alzheimer's disease or Parkinson's disease with dementia.
Recent trials using cholinesterase inhibitors, such as tacrine, have shown promise for partial reversal of senile dementia of the Alzheimer type in a few patients. Ott et al., in Clinical Neuropharmacology 15(4):322-325, 1992, treated a patient with Alzheimer's disease with tacrine, which has traditionally been used to treat Alzheimer's dementia. The individual originally presented as Alzheimer's disease developed other symptoms, including extrapyramidal features. This patient, along with three other patients with a typical presentation of Alzheimer's disease responded with improvement or stabilization in cognitive ability and activities of daily living score. Another case, again clinically and neuropathologically diagnosed as Alzheimer's disease, responded initially, but this response was not sustained. This paper clearly implies, then, that increasing rigidity would be expected in a Parkinson patient to whom tacrine is administered, since the tacrine caused rigidity in an Alzheimer's patient. This would certainly deter a practicing neurologist from prescribing this type of drug for a patient suffering from Parkinson's disease, as any medication that increases rigidity would be contraindicated for parkinsonian patients.
Treatment of dementia in parkinsonian patients with cholinomimetic drugs presents a dilemma, since the movement disorder would be expected to worsen with treatment with tacrine or similar anticholinesterase medications. It should be noted that Ott et al., ibid., treated an Alzheimer's patient with mild parkinsonism, rather than a patient whose primary presentation was Parkinson's disease, with a combination of levodopa and tacrine. The dramatic increase in tremor, as well as induction of gait dysfunction and subjective feelings of rigidity, were attributed to the cholinergic effects of acetylcholinesterase inhibitors on the striatum. The increased tremor responded to addition of levodopa as well as to decrease in tacrine dosage with restoration of baseline function after either maneuver. After two months of treatment with levodopa, the gait function and bradykinesia appeared to improve, suggesting that the patient had developed some tolerance to the extra-pyramidal effects of tacrine. It had not been determined whether such tolerance actually occurs and whether it would be sustained, or whether levodopa actually improved it.
Perry et al., in Annals New York Academy of Sciences pp. 197-202, report examining cholinergic and monoaminergic (dopaminergic and serotonergic) activities in postmortem brain tissue in senile dementia of Lewy body type, Parkinson's disease, and Alzheimer's disease. The quantitative data they obtained suggested that although extra-pyramidal symptoms relate to striatal levels of dopamine, cognitive impairment was most closely associated with cholinergic but not monoaminergic deficits in temporal and archicortical areas. For example, hallucinations, frequently manifested in Lewy body dementia, appear to be related to an extensive cholinergic deficit in temporal neocortex and the resulting imbalance between decreased cholinergic and relatively preserved serotonergic activities.
As with Lewy body dementia, Parkinson's disease is associated with a cholinergic deficit, which may be more profound than that seen in senile dementia of the Alzheimer type (SDAT). Later stages of Parkinson's disease are characterized by a debilitating confusional state with psychotic features. Although this may, to some extent, overlap symptoms of SDAT, there is presumably a high incidence of pure Lewy body dementia in parkinsonian patients with dementia. As anticholinergic drugs have mild antiparkinsonian effects, however, it has been assumed that a procholinergic drug will worsen the characteristic rigidity of Parkinson's disease.